Dan J. Fintel

Randomised trial of coronary intervention with antibody against platelet IIb/IIIa iritegrin for reduction of clinical restenosis: results at six months

Abstract Restenosis after coronary angioplasty occurs in at least 30% of patients in the first six months and, as yet, there is no known treatment to decrease this event. We tested a monoclonal antibody Fab fragment (c7E3) directed against the platelet glycoprotein IIb/IIIa integrin, the receptor mediating the final common pathway of platelet aggregation, to see whether it reduced the frequency of clinical restenosis. Patients who had unstable angina, recent or evolving myocardial infarction, or high-risk angiographic morphology, were randomised to receive c7E3 bolus and a 12 hour infusion of c7E3 (708 patients), c7E3 bolus and placebo infusion (695 patients), or placebo bolus and placebo infusion (696 patients). With maintenance of the double-blind state, patients were followed-up for at least 6 months to determine the need for repeat angioplasty or surgical coronary revascularisation and the occurrence of ischaemic events. By 30 days, 12·8% of placebo bolus/placebo infusion patients had had a major ischaemic event (death, myocardial infarcton, urgent revascularisation), compared with 8·3% of c7E3 bolus/c7E3 infusion patients, yielding a 4·5% difference (35% reduction, p=0·008). At 6 months, the absolute difference in patients with a major ischaemic event or elective revascularisation was 8·1% between placebo bolus/ placebo infusion and c7E3 bolus/c7E3 infusion patients (35·1% vs 27·0%; 23% reduction p=0·001). The favourable long-term effect was mainly due to less need for bypass surgery or repeat angioplasty in patients with an initial successful procedure, since need for repeat target vessel revascularisation was 26% less for c7E3 bolus/c7E3 infusion than for placebo treatment (16·5% vs 22·3%; p=0·007). The c7E3 bolus/placebo infusion group had an intermediate outcome which was not significantly better than that of the placebo bolus/placebo infusion group. These results extend the benefit of c7E3 bolus/c7E3 infusion from reducing abrupt closure and acute-phase adverse outcomes to a diminished need for subsequent coronary revascularisation procedures. Because this therapy carries a risk of bleeding complications and has been studied only in high-risk angioplasty patients, further evaluation is needed before it can be applied to other patient groups.

Reproducibility and Relation to Mean Heart Rate of Heart Rate Variability in Normal Subjects and in Patients with Congestive Heart Failure Secondary to Coronary Artery Disease

Before heart rate (HR) variability can be used for predictive purposes in the clinical setting, day-to-day variation and reproducibility need to be defined as do relations to mean HR. HR variability and mean HR were therefore determined in 2 successive 24-hour ambulatory electrocardiograms obtained from 33 normal subjects (age 34 +/- 7 years, group I), and 22 patients with coronary disease and stable congestive heart failure (CHF) (age 59 +/- 7 years, group II). Three measures were used: (1) SDANN (standard deviation of all mean 5-minute normal sinus RR intervals in successive 5-minute recording periods over 24 hours); (2) SD (the mean of the standard deviation of all normal sinus RR intervals in successive 5-minute recording periods over 24 hours); and (3) CV (coefficient of variation of the SD measure), a new measure that compensates for HR effects. Group mean HR was higher and HR variability lower in group II than in group I (80 +/- 10 vs 74 +/- 9 beats/min, p less than 0.04). Mean group values for HR and HR variability showed good correlations between days 1 and 2 (mean RR, r = 0.89, 0.97; SDANN, r = 0.87, 0.87; SD, r = 0.93, 0.97; CV, r = 0.95, 0.97 in groups I and II, respectively). In contrast, considerable individual day-to-day variation occurred (group I, 0 to 46%; group II, 0 to 51%). Low HR variability values were more consistent than high values. SDANN and SD correlated moderately with HR in both groups (r = 0.50 to 0.64). The CV measure minimizes HR effects on HR variability.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved diagnostic performance of exercise thallium-201 single photon emission computed tomography over planar imaging in the diagnosis of coronary artery disease: a receiver operating characteristic analysis

Qualitative interpretation of tomographic and planar scintigrams, a five point rating scale and receiver operating characteristic analysis were utilized to compare single photon emission computed tomography and conventional planar imaging of myocardial thallium-201 uptake in the accuracy of the diagnosis of coronary artery disease and individual vessel involvement. One hundred twelve patients undergoing cardiac catheterization and 23 normal volunteers performed symptom-limited treadmill exercise, followed by stress and redistribution imaging by both tomographic and planar techniques, with the order determined randomly. Paired receiver operating characteristic curves revealed that single photon emission computed tomography was more accurate than planar imaging over the entire range of decision thresholds for the overall detection and exclusion of coronary artery disease and involvement of the left anterior descending and left circumflex coronary arteries. Tomography offered relatively greater advantages in male patients and in patients with milder forms of coronary artery disease, who had no prior myocardial infarction, only single vessel involvement or no lesion greater than or equal to 50 to 69%. Tomography did not appear to provide improved diagnosis in women or in detection of disease in the right coronary artery. Although overall detection of coronary artery disease was not improved in patients with prior myocardial infarction, tomography provided improved identification of normal and abnormal vascular regions, particularly of the left anterior descending and circumflex artery regions. These results indicate that single photon emission computed tomography provides improved diagnostic performance compared with planar imaging in many clinical subgroups, and suggest that it represents the diagnostic imaging procedure of choice in exercise thallium-201 perfusion studies.

Insurance Coverage and Care of Patients with Non–ST-Segment Elevation Acute Coronary Syndromes

Context Medicaid and Medicare reimbursement is typically lower than that of private insurance. This might affect access to care for Medicaid and Medicare patients. Contribution The authors studied the care received for nonST-segment elevation acute coronary syndromes by 37345 patients younger than age 65 years and 59550 patients age 65 years or older. Compared with privately insured patients, Medicaid patients received fewer guideline-recommended services at admission or discharge and experienced greater delays in receiving invasive procedures. Differences for Medicare patients were fewer and smaller, although delays were common. The in-hospital mortality rate was higher in Medicaid patients but not Medicare patients. Cautions The authors could not assess the appropriateness of invasive procedures, socioeconomic status, severity of comorbid conditions, or patient preferences. The Editors For patients with nonST-segment elevation acute coronary syndromes (NSTE ACS), novel therapeutic approaches, such as low-molecular-weight heparin, glycoprotein (GP) IIb/IIIa inhibitors, and early invasive management strategies, have been shown to have beneficial effects and have been incorporated into practice guidelines of the American College of Cardiology and American Heart Association (ACC/AHA) (15). However, the extent to which these and other guideline-recommended therapies are reaching all segments of the U.S. population is unclear. Specifically, although U.S. Medicaid and Medicare programs often provide coverage for patients with limited incomes, reimbursements to health care providers by these programs may differ from those of private insurance plans (6). Because novel therapies and invasive cardiac procedures for NSTE ACS are costly, differential patterns of reimbursement in Medicaid and Medicare programs may affect treatment patterns and guideline adherence. Thus, we first evaluated patients younger than age 65 years with NSTE ACS from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) quality improvement initiative to determine the impact of primary Medicaid coverage on the use of guideline-recommended medications, invasive cardiac procedures, and in-hospital clinical outcomes compared with that of patients with primary health maintenance organization (HMO) or private insurance coverage. We then performed a similar comparison between patients 65 years of age or older with primary Medicare coverage and patients of the same age with primary HMO or private insurance coverage. Furthermore, we sought to determine the degree to which any differences in care patterns and outcomes resulted from differences in clinical characteristics or to preferential care of Medicare or Medicaid patients at lower-quality hospitals. Methods Patient Inclusion Criteria Patients with NSTE ACS were included if they had ischemic symptoms at rest within 24 hours of presentation and high-risk features, including ST-segment depression levels of 0.5 mm or more, transient ST-segment elevation levels of 0.5 to 1.0 mm (lasting for less than 10 minutes), positive cardiac markers (elevated troponin I or T levels, creatine kinase [CK]-MB levels, or both greater than the upper limit of normal for the local laboratory assay) or both. Data Collection CRUSADE is a voluntary quality improvement initiative that began in November 2001 (with retrospective data collection from January 2001), and data collection is ongoing. At the beginning of the project, queries were sent to a geographically diverse sample of hospitals. Participation was voluntary. Because data were collected retrospectively and do not include any patient identifying information, informed consent was waived. The local institutional review board at each hospital approved participation in CRUSADE. No specific quality initiative was implemented in all institutions, although sites were provided with sample order sets and discharge forms to use at their discretion. Data on hospital characteristics were obtained from the American Hospital Association database. Participating institutions were instructed to submit consecutive eligible patients to the CRUSADE database. Data were abstracted directly from the medical chart by trained data collectors using standardized definitions. Administrative claims data were not abstracted for this study. Abstracted variables included demographics, clinical characteristics, medical therapies and major contraindications, use and timing of cardiac procedures, laboratory results, and in-hospital outcomes. Insurance status was defined as the patients primary insurance provider. Data abstractors at the participating sites were aware of the patients primary insurance status and were given specific definitions for categorization of primary insurance status. Health maintenance organization and private insurance were defined as any health insurance provided by a commercial plan, regardless of restrictions or payment arrangements. Medicare coverage was defined as the federal health care plan that reimburses hospitals and physicians for the care of elderly patients 65 years of age or older. Medicaid coverage was defined as state-administered plans jointly funded by state and federal funding mechanisms providing primary coverage to patients younger than 65 years of age who cannot finance their own medical expenses or who have qualifying comorbid conditions. Medicare or Medicaid coverage was recorded on the data collection form as a single, dichotomous variable until November 2003; thus, we could not clearly specify primary Medicaid versus Medicare coverage for patients included in CRUSADE before this time. Self or no insurance coverage was defined as when individuals were the sole payers, regardless of ability to pay. Self or no coverage was recorded on the data collection form as a single, dichotomous variable, and we excluded patients in this category from the analysis because of the inconsistent reporting of this variable. Military or Veterans Affairs Medical Center coverage was used to describe patients with a military or Veterans Administration health plan. This group also was excluded from the primary analysis because of the small number of patients covered by these programs. Data Accuracy Routine procedures have been established to maintain and monitor the quality of the CRUSADE database. At data entry and during quarterly quality control procedures, values that exceed expected ranges are flagged and excluded from analysis. In addition, sites receive a quarterly report summarizing any data quality problems observed in their submitted data. In September 2002, CRUSADE formally assessed the reliability of data abstraction. Sites and records were randomly selected. Study coordinators from one fourth of CRUSADE hospitals were contacted and asked to send the CRUSADE Coordinating Center copies of medical records without patient identifiers for audit by CRUSADE project officials. In addition to selected clinical characteristics, audited variables included all medical therapies, procedures, and in-hospital clinical events. The overall accuracy of audited case report forms compared with medical records was 94.8%. The overall degree of missing data averaged approximately 5% across all collected data elements. Of note, such variables as age and sex were missing in fewer than 0.5% of all audited cases. In addition, we reviewed the degree of missing variables among 119257 patients included in the overall database through 30 September 2004 and determined that key clinical characteristics, such as age (0.18%), sex (0.29%), race (1.45%), insurance status (1.0%), and such clinical outcomes as death (1.33%) and reinfarction (1.29%) were infrequently missing on data collection forms. Analysis Cohorts A total of 138719 patients was entered into the CRUSADE database from January 2001 through March 2005 at 521 U.S. hospitals. For the Medicaid analysis, we excluded 80423 patients 65 years of age or older or who had missing age values, 11438 patients from hospitals without percutaneous and surgical revascularization capabilities, 2587 patients with Medicare listed as the primary payer, 413 patients with insurance status listed as military or Veterans Affairs Medical Center, 6025 patients with insurance status listed as self or none, and 488 patients with missing data on insurance status. The total population for the Medicaid analysis was thus 37345 patients from 358 hospitals. For the Medicare analysis, we excluded 58537 patients younger than 65 years of age or who had missing age values, 18922 patients from hospitals without percutaneous and surgical revascularization capabilities, 214 patients with Medicaid as the primary payer, 275 patients with insurance status listed as military or Veterans Affairs Medical Center, 756 patients with insurance status listed as self or none, and 465 patients with missing data on insurance status. The total population for the Medicare analysis was thus 59550 patients from 359 hospitals. Statistical Analysis We evaluated patient baseline demographics, clinical characteristics, in-hospital care patterns, and in-hospital outcomes for patients younger than 65 years of age with Medicaid as the primary payer compared with those younger than 65 years of age with HMO or private insurance as the primary payer. Likewise, we compared patients 65 years of age or older with Medicare as the primary payer with those 65 years of age or older with HMO and private insurance as the primary payer. Health maintenance organization refers to private HMO coverage in our analysis. We were unable to distinguish whether Medicare or Medicaid coverage was received through a managed care program. Also, we could not ascertain whether supplemental insurance coverage was available for Medicare patients older than 65 years of age. We performed these comparisons within separate age categories beca

Use of and inhospital outcomes after early clopidogrel therapy in patients not undergoing an early invasive strategy for treatment of non-ST-segment elevation myocardial infarction: results from Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines (CRUSADE).

BACKGROUND Although current guidelines recommend early initiation of clopidogrel in patients with non-ST-segment elevation myocardial infarction (NSTEMI), the degree to which it has been adopted in clinical practice remains unclear. We sought to determine patterns of early (<24 hours of arrival) clopidogrel use and its association with clinical outcomes in patients with NSTEMI not undergoing early percutaneous intervention (PCI). METHODS Using data from the CRUSADE initiative, after the exclusion of patients who underwent PCI within 24 hours of arrival, we studied trends in early clopidogrel use among 93,045 patients with NSTEMI. Multivariable logistic regression models were used to determine the association between early clopidogrel treatment and inhospital outcomes. RESULTS A total of 38.6% of the NSTEMI patients not undergoing PCI within 24 hours of arrival received early clopidogrel. Adjusted inhospital mortality rate was lower in the early clopidogrel group compared to the group that did not receive it on admission (odds ratio 0.68, 95% CI 0.61-0.77). The rate of major bleeding in patients not undergoing coronary artery bypass surgery was similar among the groups treated with and without early clopidogrel (9.5% vs 9.5%, P = .90). CONCLUSIONS Until recently, up to 50% of NSTEMI patients in contemporary practice in the United States not undergoing PCI within 24 hours of arrival in the United States are not treated according to guideline recommendations. Among a high-risk NSTEMI population not undergoing PCI within 24 hours of arrival, the nonrandomized short-term use of clopidogrel is associated with a lower risk of inhospital mortality without an increased risk of major bleeding.

The effect of clonidine on the cessation of cigarette smoking

The effect of clonidine on smoking cessation was studied by randomly assigning 186 smokers in a double‐blind fashion to either placebo or clonidine. Abstinence from smoking was reported more frequently by subjects receiving clonidine, but the difference was statistically significant only at the end of the first week (34.4% vs 21.5%; p < 0.05). Bothersome side effects were common and resulted in the early discontinuation of the study medication by 23 of the subjects taking clonidine and eight taking placebo (p < 0.05). Although this study did not demonstrate a significant effect of clonidine on smoking cessation, a beneficial trend was detected and therefore further trials with transcutaneous delivery of this agent in combination with behavior modification techniques are warranted.

Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options

Clinical presentations of atherothrombotic vascular disease, such as acute coronary syndromes, ischemic stroke or transient ischemic attack, and symptomatic peripheral arterial disease, are major causes of morbidity and mortality worldwide. Platelet activation and aggregation play a seminal role in the arterial thrombus formation that precipitates acute manifestations of atherothrombotic disease. As a result, antiplatelet therapy has become the cornerstone of therapy for the prevention and treatment of atherothrombotic disease. Dual antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor inhibitor, such as clopidogrel or prasugrel, is the current standard-of-care antiplatelet therapy in patients with acute coronary syndromes managed with an early invasive strategy. However, these agents are associated with several important clinical limitations, including significant residual risk for ischemic events, bleeding risk, and variability in the degree of platelet inhibition. The residual risk can be attributed to the fact that aspirin and P2Y12 inhibitors block only the thromboxane A2 and ADP platelet activation pathways but do not affect the other pathways that lead to thrombosis, such as the protease-activated receptor-1 pathway stimulated by thrombin, the most potent platelet agonist. Bleeding risk associated with aspirin and P2Y12 inhibitors can be explained by their inhibitory effects on the thromboxane A2 and ADP pathways, which are critical for protective hemostasis. Interpatient variability in the degree of platelet inhibition in response to antiplatelet therapy may have a genetic component and contribute to poor clinical outcomes. These considerations underscore the clinical need for therapies with a novel mechanism of action that may reduce ischemic events without increasing the bleeding risk.

Anistreplase versus alteplase in acute myocardial infarction: Comparative effects on left ventricular function, morbidity and 1-day coronary artery patency

OBJECTIVES This double-blind, randomized, multicenter trial was designed to compare the effects of treatment with anistreplase (APSAC) and alteplase (rt-PA) on convalescent left ventricular function, morbidity and coronary artery patency at 1 day in patients with acute myocardial infarction. BACKGROUND Anistreplase (APSAC) is a new, easily administered thrombolytic agent recently approved for treatment of acute myocardial infarction. Alteplase (rt-PA) is a rapidly acting, relatively fibrin-specific thrombolytic agent that is currently the most widely used agent in the United States. METHODS Study entry requirements were age less than or equal to 75 years, symptom duration less than or equal to 4 h, ST segment elevation and no contraindications. The two study drugs, APSAC, 30 U/2 to 5 min, and rt-PA, 100 mg/3 h, were each given with aspirin (160 mg/day) and intravenous heparin. Prespecified end points were convalescent left ventricular function (rest/exercise), clinical morbidity and coronary artery patency at 1 day. A total of 325 patients were entered, stratified into groups with anterior (37%) or inferior or other (63%) acute myocardial infarction, randomized to receive APSAC or rt-PA and followed up for 1 month. RESULTS At entry, patient characteristics in the two groups were balanced. Convalescent ejection fraction at the predischarge study averaged 51.3% in the APSAC group and 54.2% in the rt-PA group (p less than 0.05); at 1 month, ejection fraction averaged 50.2% versus 54.8%, respectively (p less than 0.01). In contrast, ejection fraction showed similar augmentation with exercise at 1 month after APSAC (+4.3% points) and rt-PA (+4.6% points), and exercise times were comparable. Coronary artery patency at 1 day was high and similar in both groups (APSAC 89%, rt-PA 86%). Mortality (APSAC 6.2%, rt-PA 7.9%) and the incidence of other serious clinical events, including stroke, ventricular tachycardia, ventricular fibrillation, heart failure within 1 month, recurrent ischemia and reinfarction were comparable in the two groups; and mechanical interventions were applied with equal frequency. A combined clinical morbidity index was determined and showed a comparable overall outcome for the two treatments. CONCLUSIONS Convalescent rest ejection fraction was high after both therapies but higher after rt-PA; other clinical outcomes, including exercise function, morbidity index, and 1-day coronary artery patency, were favorable and comparable after APSAC and rt-PA.

Overweight and obesity: The pathogenesis of cardiometabolic risk

Obesity, particularly abdominal adiposity, is increasingly recognized as a cause of elevated cardiometabolic risk--the risk of developing type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). The predominate mechanisms appear to involve the promotion of insulin resistance, driven largely by excess free fatty acids secreted by an expanded adipose tissue mass, and the development of an inflammatory milieu due to increased secretion of inflammatory cytokines and adipokines from adipose tissue. Key proinflammatory cytokines secreted by adipocytes include tumor necrosis factor-alpha, interleukin-6, leptin, resistin, and plasminogen activator inhibitor-1. All have been variously associated with hyperinsulemia, hyperglycemia, insulin resistance, diabetes, and endothelial dysfunction, as well as plaque development, progression, and rupture. Adiponectin, another important adipocyte, has protective cardiometabolic actions; however, adiponectin levels decline with increasing obesity. Understanding the role of obesity in the pathogenesis of cardiometabolic risk is crucial for the development of treatment strategies that will provide maximum benefit for patients with, or at risk for, type 2 DM and CVD.

Risk factors in siblings of people with premature coronary heart disease

Prior studies of the contribution of coronary disease risk factors to familial aggregation of premature coronary disease may have underestimated risk factors by relying on self-reported risk factor prevalence levels or, when risk factors have been measured, by using cut points in excess of the 90th percentile. To determine the actual prevalence of hyperlipidemia, hypertension and diabetes, and the awareness of these coronary risk factors in unaffected family members, 150 apparently coronary disease-free siblings of 86 people who had documented coronary disease before 60 years of age were studied. All subjects participated in a 1 day screening preceded by a self-administered risk factor questionnaire and a personal interview. Participation of both the index patients and siblings exceeded 86%. With the use of nationally established recommendations for blood pressure and lipids, which are based on coronary disease risk curves, screening revealed that 48% of brothers and 41% of sisters were hypertensive, 45% of brothers and 22% of sisters had a lipid abnormality, 38% of siblings were current cigarette smokers and 4.7% were diabetic. Two or more risk factors were present in 42% of brothers and 26% of sisters. More than 75% of siblings had one or more risk factors that would require intervention. When compared with a race-, gender- and age-matched reference population from the Lipid Research Clinics Prevalence Study, distributions for blood pressure and for total and low density lipoprotein cholesterol were higher for the siblings in every gender and age group.(ABSTRACT TRUNCATED AT 250 WORDS)